Use of a scaffold peptide in the biosynthesis of amino acid–derived natural products

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Science  19 Jul 2019:
Vol. 365, Issue 6450, pp. 280-284
DOI: 10.1126/science.aau6232

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Growing independently

Bacteria produce natural products with a range of functions. A major family comprises ribosomally synthesized and posttranslationally modified peptides. Ting et al. identify a biosynthetic pathway in which a natural product is derived from an amino acid that is added to a ribosomally synthesized peptide independent of the ribosome. This biosynthetic paradigm is used in the synthesis of thiaglutamate and ammosamides, and the finding of related gene clusters suggests that the strategy may be used more widely.

Science, this issue p. 280


Genome sequencing of environmental bacteria allows identification of biosynthetic gene clusters encoding unusual combinations of enzymes that produce unknown natural products. We identified a pathway in which a ribosomally synthesized small peptide serves as a scaffold for nonribosomal peptide extension and chemical modification. Amino acids are transferred to the carboxyl terminus of the peptide through adenosine triphosphate and amino acyl-tRNA–dependent chemistry that is independent of the ribosome. Oxidative rearrangement, carboxymethylation, and proteolysis of a terminal cysteine yields an amino acid–derived small molecule. Microcrystal electron diffraction demonstrates that the resulting product is isosteric to glutamate. We show that a similar peptide extension is used during the biosynthesis of the ammosamides, which are cytotoxic pyrroloquinoline alkaloids. These results suggest an alternative paradigm for biosynthesis of amino acid–derived natural products.

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